EP3738582A1 - Solid particle, preparation method therefor, and pharmaceutical composition containing solid particle - Google Patents

Solid particle, preparation method therefor, and pharmaceutical composition containing solid particle Download PDF

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Publication number
EP3738582A1
EP3738582A1 EP18900355.1A EP18900355A EP3738582A1 EP 3738582 A1 EP3738582 A1 EP 3738582A1 EP 18900355 A EP18900355 A EP 18900355A EP 3738582 A1 EP3738582 A1 EP 3738582A1
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Prior art keywords
solid microparticle
solid
accounting
percentages
propylene glycol
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German (de)
French (fr)
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EP3738582A4 (en
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Liang Chang Dong
Wenbo Ma
Lin Wang
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Shanghai Wd Pharmaceutical Co Ltd
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Shanghai Wd Pharmaceutical Co Ltd
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Publication of EP3738582A1 publication Critical patent/EP3738582A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate

Definitions

  • the present invention relates to a solid microparticle, a preparation method therefor and a pharmaceutical composition containing the same.
  • Avodart® soft gelatin capsules manufactured by Glaxo Smithkline Pharmaceuticals are used for treating benign prostatic hyperplasia (BPH) of men's enlarged prostate.
  • Avodart®'s active ingredient is dutasteride.
  • Dutasteride is a selective steroid 5a-reductase inhibitor, and 5a-reductase is an endoenzyme that can convert testosterone to DHT.
  • Dutasteride has a chemical name of (5 ⁇ ,17 ⁇ )- N - ⁇ 2,5-bis(trifluoromethyl)phenyl ⁇ -3-oxo-4-azaandrost-1-ene-17-carboxam ide, the empirical formula of which is C 27 H 30 F 6 N 2 O 2 , molecular weight of which is 528.5, and the structural formula of which is shown as follows:
  • Dutasteride is a white to pale yellow powder with a melting point of 242 °C to 250 °C. It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water.
  • Hydrophobic active pharmaceutical ingredients such as dutasteride
  • active pharmaceutical agents such as dutasteride
  • APIs active pharmaceutical agents
  • Avodart® soft gelatin capsule contains 0.5 mg dutasteride, which is dissolved in a mixture of caprylic/capric mono-/di-glyceride and dibutylhydroxytoluene.
  • U.S. patent application 20130052263 discloses a formula capable of increasing the solubility of hydrophobic compounds including dutasteride.
  • U.S. Patent 9,622,981 discloses a liquid-filled hard gelatin capsule formulation that can reduce the manufacturing cost of soft capsules while maintain the bioavailability and stability of the soft gel dosage form.
  • the liquid-filled hard capsules require a sealing step to prevent potential liquid leakage during manufacturing and storing period.
  • the moisture in the hard capsules will migrate to the filled liquid formulation, resulting in a decrease in the moisture content of the hard capsules, which may cause the hard capsules to crack.
  • U.S. Patent 9,005,608 discloses a formulation for delivering the beneficial medicament Coenzyme Q (CoQ10), and the recrystallisation of dissolved CoQ10 can be prevented by incorporating a supersaturated self-emulsifying formula of CoQ10 into the pores of porous solid particles.
  • Jalyn® capsules manufactured by Glaxo Smithkline Pharmaceuticals, is a pharmaceutical composition of dutasteride and tamsulosin, which can be used for treating benign prostatic hyperplasia (BPH). Tamsulosin is an ⁇ 1A adrenergic receptor antagonist.
  • Each Jalyn® capsule contains dutasteride soft gelatin capsules and tamsulosin hydrochloride pills, and the capsules and pills are encapsulated in hard shell capsules of # 00 size. Although the combined product showed better treatment efficacy than the individual products, the # 00 size of Jalyn® capsules reached the maximum value recommended by the FDA. Therefore, they are difficult to be swallowed by BPH patients, especially elderly patients.
  • the technical problem to be solved by the present invention is to provide a solid microparticle, a preparation method therefor and a pharmaceutical composition containing the same to overcome the disadvantages of the hydrophobic active pharmaceutical ingredients (active pharmaceutical agents, APIs) in the prior art, such as dutasteride, etc., which have low bioavailability, large dosage form size, poor patient compliance, etc..
  • the solid microparticle can effectively improve solubility of APIs and dissolution rate of medicaments, and can effectively improve the problems of easy cross-linking of soft capsules of commercialized products Avodart® and Jalyn® and oversized dosage form of Jalyn® simultaneously.
  • the present invention provides a solid microparticle, which comprises porous solid particles and a non-aqueous liquid formula
  • the non-aqueous liquid formula comprises 0.10% to 4.00% hydrophobic active pharmaceutical ingredient, 28.00% to 99.90% hydrophobic liquid solubilizer, 0 to 70.00% nonionic surfactant, and 0 to 1.00% antioxidant, the percentages refer to the weight percentages accounting for the non-aqueous liquid formula
  • the hydrophobic liquid solubilizer comprises medium-chain mono-/di- glyceride, and/or propylene glycol fatty acid monoester.
  • the content of the hydrophobic active pharmaceutical ingredient may be 0.10% to 2.00% or 0.18% to 2.00%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the content of the hydrophobic active pharmaceutical ingredient may be 0.18%, 0.83%, 0.84%, 0.91%, 0.93%, 0.99%, 1.00%, 1.08%, 1.09%, 1.23%, 1.25%, 1.64%, 1.67%, 1.96% or 2.00%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the content of the hydrophobic liquid solubilizer may be 32.50% to 99.07%, 39.60% to 99.01%, or 49.50% to 74.26%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the content of the hydrophobic liquid solubilizer may be 32.50%, 39.60%, 46.00%, 47.06%, 49.02%, 49.18%, 49.50%, 59.41%, 59.87%, 60.67%, 60.83%, 61.73%, 63.00%, 65.57%, 72.55%, 73.51%, 74.26%, 75.00%, 82.16%, 82.43%, 83.33%, 98.27%, 98.79%, 99.01% or 99.07%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the content of the nonionic surfactant when the content of the nonionic surfactant is not 0, the content of the nonionic surfactant may be 15.00% to 66.67%, 24.51% to 59.41%, or 24.75% to 49.50%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the content of the nonionic surfactant when the content of the nonionic surfactant is not 0, the content of the nonionic surfactant may be 15.00%, 16.43%, 16.49%, 23.75%, 24.51%, 24.75%, 27.27%, 32.79%, 36.00%, 37.04%, 38.33%, 38.79%, 39.60%, 48.99%, 49.18%, 49.50%, 50.98%, 52.00%, 59.41% or 66.67%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the content of the antioxidant when the content of the antioxidant is not 0, the content of the antioxidant may be 0.10% to 1.00% or 0.17% to 0.83%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the content of the antioxidant when the content of the antioxidant is not 0, the content of the antioxidant may be 0.17%, 0.28%, 0.33%, 0.51%, 0.83%, or 1.00%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the non-aqueous liquid formula comprises 0.10% to 2.00% hydrophobic active pharmaceutical ingredient, 97.00% to 99.80% medium-chain mono-/di- glyceride, and 0.10% to 1.00% antioxidant, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the non-aqueous liquid formula comprises 0.10% to 4.00% hydrophobic active pharmaceutical ingredient, 95.00% to 99.90% propylene glycol fatty acid monoester, and 0 to 1.00% antioxidant, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the weight ratio of the porous solid particle to the non-aqueous liquid formula may be a conventional ratio in the art, preferably 2: 1 to 3: 1, and more preferably 2: 1.
  • the solid microparticle comprises 0.025% to 3.00% hydrophobic active pharmaceutical ingredient, 5.00% to 59.90% hydrophobic liquid solubilizer, and 0 to 45.00% nonionic surfactant, 0 to 0.60% antioxidant, and 40.00% to 75.00% porous solid particle, and the percentages refers to the weight percentages accounting for the solid microparticle.
  • the content of the hydrophobic active pharmaceutical ingredient may be 0.10% to 2.00%, such as 0.33%, 0.10% or 0.5%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the content of the hydrophobic liquid solubilizer may be 5.00% to 39.90%, 11.50% to 35.00% or 13.20% to 33.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the content of the hydrophobic liquid solubilizer may be 11.50%, 12.00%, 13.20%, 15.00%, 16.34%, 16.50%, 20.00%, 24.50%, 24.75%, 25.00%, 30.00%, 31.50%, 33.00%, 35.00%, 35.50%, 35.70%, 36.40%, 36.50% or 39.90%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the content of the hydrophobic active pharmaceutical ingredient is preferably 0.025% to 1.20%, and the content of the medium-chain mono-/di-glyceride is 24.50% to 59.90%, for example, 25.00% or 30.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the hydrophobic liquid solubilizer is propylene glycol fatty acid monoester
  • the content of the hydrophobic active pharmaceutical ingredient is preferably 0.025% to 2.40%
  • the content of the propylene glycol fatty acid monoester is preferably 23.00% to 59.90%, such as 24.50%, 24.75%, 25.00%, 30.00%, 31.50%, 33.00%, 35.00%, 35.50%, 35.70%, 36.40%, 36.50% or 39.90%, and the percentages refer to the weight percentages account for the solid microparticle.
  • the content of the nonionic surfactant may be 0 to 40.00%.
  • the content of the nonionic surfactant may be 4.50% to 40.00%, 8.17% to 19.80%, or 8.25% to 16.50%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the content of the nonionic surfactant when the content of the nonionic surfactant is not 0, the content of the nonionic surfactant may be 4.50%, 5.00%, 8.17%, 8.25%, 9.50%, 10.00%, 13.00%, 15.00%, 16.33%, 16.50%, 18.00%, 19.80%, 20.00%, 23.00% or 40.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the content of the antioxidant when the content of the antioxidant is not 0, the content of the antioxidant may be 0.025% to 0.60%, such as 0.10%, 0.30%, or 0.33%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the content of the porous solid particles may be 40.00% to 75.00% or 60.00% to 70.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the content of the porous solid particles may be 40.00%, 40.70%, 45.00%, 49.50%, 50.00%, 59.50%, 60.00%, 63.67%, 64.57%, 64.67%, 66.67%, 69.5%, 69.57%, 69.67%, 70.00%, 74.50% or 75.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the content of the non-aqueous liquid formula may be 25.00% to 60.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the content of the non-aqueous liquid formula may be 25.00%, 25.50%, 30.00%, 30.33%, 30.43%, 30.50%, 33.33%, 35.33%, 35.43%, 36.33%, 40.00%, 40.50%, 50.00%, 50.50%, 55.00%, 59.30% or 60.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • the hydrophobic active pharmaceutical ingredient may be one or more than one selected from dutasteride, finasteride, carvedilol, isotretinoin, fentanyl, sufentanil, zaleplon, testosterone, progesterone, hydroxyprogesterone, norprogesterone, norgestrel, chlorothiazide, furosemide, prednisolone, hydrocortisone, betamethasone, danazol, phenytoin, digoxin, dipyridamole, mefenamic acid, griseofulvin, ketoconazole, itraconazole, glibenclamide, and ⁇ -carotene, preferably dutasteride.
  • the medium-chain mono-/di-glyceride refers to an ester chain formed by the esterification of glycerol with one or two C 6 -C 12 fatty acids.
  • Commercially available medium-chain mono-/di- glyceride may comprises Capmul @ products manufactured by Abitec.
  • the hydrophobic liquid solubilizer comprises medium-chain mono-/di- glyceride
  • the medium-chain of the medium-chain mono-/diglyceride is preferably a C 8 -C 10 fatty acid chain.
  • the medium-chain mono-/diglyceride is preferably mono-/di- caprylate/caprate (Capmul MCM), such as caprylic capric mono-/di- glyceride.
  • the propylene glycol fatty acid monoester refers to an ester chain formed by esterification of propylene glycol with a C 6 -C 12 fatty acid.
  • the hydrophobic liquid solubilizer comprises propylene glycol fatty acid monoester
  • the fatty acid of the propylene glycol fatty acid monoester is preferably a C 8 -C 12 fatty acid chain.
  • the propylene glycol fatty acid monoester is preferably propylene glycol monolaurate (type II) (LAUROGLYCOL 90) and/or propylene glycol monocaprylate (type II) (CAPRYOL 90), more preferably propylene glycol monocaprylate (type II) (CAPRYOL 90).
  • the type of the nonionic surfactant is preferably PEGylated type and/or polyol type, and more preferably PEGylated type.
  • the PEGylated nonionic surfactant is preferably polyoxyethylene 35 castor oil (Kolliphor® ELP) and/or caprylocaproyl polyoxylglycerides (LABASOL ALF).
  • polyol type nonionic surfactant is preferably polysorbate 80 (TM).
  • the antioxidant may be a conventional antioxidant in the art, preferably dibutylhydroxytoluene (BHT) and/or butylhydroxyanisole (BHA), and more preferably dibutylhydroxytoluene (BHT).
  • BHT dibutylhydroxytoluene
  • BHA butylhydroxyanisole
  • the porous solid particles may be a kind of conventional porous carrier in the art, and are preferably one or more than one of calcium hydrogen phosphate (Fujicalin), magnesium aluminometasilicate (Neusilin) and silicon dioxide, and more preferably calcium hydrogen phosphate (Fujicalin).
  • the porous solid particles have a specific surface area of >30 m 2 /g, and adsorb at least 0.40 mL/g the non-aqueous liquid formula, while maintaining flowability simultaneously.
  • the solid microparticle comprise 0.0025% to 3.00% hydrophobic active pharmaceutical ingredient, 5.00% to 59.90% hydrophobic liquid solubilizer, 0 to 45.00% nonionic surfactant, 0.025% to 0.60% antioxidant, and 40.00% to 75.00% porous solid particles, and the percentages refers to the weight percentages accounting for the solid microparticle.
  • the solid microparticle comprises 0.33% dutasteride, 33.00% propylene glycol monocaprylate (type II) (CAPRYOL 90), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • the solid microparticle comprises 0.33% dutasteride, 24.75% propylene glycol monocaprylate (type II) (CAPRYOL 90), 8.25% caprylocaproyl polyoxylglycerides (LABASOL ALF), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • the solid microparticle comprises 0.33% dutasteride, 16.5% propylene glycol monocaprylate (type II) (CAPRYOL 90), 16.5% caprylocaproyl polyoxylglycerides (LABASOL ALF), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • the solid microparticle comprises 0.33% dutasteride, 13.2% propylene glycol monocaprylate (type II) (CAPRYOL 90), 19.80% caprylocaproyl polyoxylglycerides (LABASOL ALF) and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • the solid microparticle comprises 0.33% dutasteride, 24.75% propylene glycol monocaprylate (type II) (CAPRYOL 90), 8.25% polyoxyethylene 35 castor oil (Kolliphor® ELP), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • the solid microparticle comprises 0.33% dutasteride, 16.50% propylene glycol monocaprylate (type II) (CAPRYOL 90), 16.50% polyoxyethylene 35 castor oil (Kolliphor® ELP), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • the solid microparticle comprises 0.33% dutasteride, 13.20% propylene glycol monocaprylate (type II) (CAPRYOL 90), 19.80% polyoxyethylene 35 castor oil (Kolliphor® ELP), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • the solid microparticle comprises 0.33% dutasteride, 24.50% propylene glycol monocaprylate (type II) (CAPRYOL 90), 8.17% polyoxyethylene 35 castor oil (Kolliphor® ELP), 0.33% dibutylhydroxytoluene (BHT), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • CAPRYOL 90 propylene glycol monocaprylate
  • Kolliphor® ELP 8.17% polyoxyethylene 35 castor oil
  • BHT dibutylhydroxytoluene
  • Fejicalin calcium hydrogen phosphate
  • the solid microparticle comprises 0.33% dutasteride, 16.34% propylene glycol monocaprylate (type II) (CAPRYOL 90), 16.33% polyoxyethylene 35 castor oil (Kolliphor® ELP), 0.33% dibutylhydroxytoluene (BHT), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid particle.
  • CAPRYOL 90 propylene glycol monocaprylate
  • Kolliphor® ELP polyoxyethylene 35 castor oil
  • BHT dibutylhydroxytoluene
  • Fejicalin calcium hydrogen phosphate
  • the invention also provides a method for preparing the solid microparticle, which comprises the following steps:
  • the mixing method may be a conventional mixing method in the art, and is preferably vortexing.
  • the porous solid particles may further comprise a glidant.
  • the glidant may be a conventional glidant in the art, and is preferably silicon dioxide.
  • the present invention also provides a pharmaceutical composition containing the solid microparticle and tamsulosin.
  • the pharmaceutical composition may be in a conventional dosage form, such as a hard capsule.
  • the preparation method of the hard capsule can be a conventional preparation method in the art, and specifically, the solid microparticle and tamsulosin are filled into two-piece hard capsules.
  • the tamsulosin is a commercially available conventional product in the art, for example, it may be tamsulosin sustained-release pellets or tamsulosin hydrochloride sustained-release pellets.
  • the pharmaceutical composition may also be used in combination, and the solid microparticle in the pharmaceutical composition are preferably dutasteride solid microparticle.
  • the pharmaceutical composition and the tamsulosin sustained-release pellets can be encapsulated in two-piece hard capsules when they are used in combination, and the size of the hard capsule is not greater than # 0.
  • tamsulosin in the pharmaceutical composition can also be replaced with a conventional therapeutic medicament in the art, as long as the therapeutic medicament does not react with the solid microparticle in the present invention and affect the pharmacological activities of the medicament and the solid particle in the present invention.
  • a solid microparticle comprises porous solid particle and a non-aqueous liquid formula.
  • the non-aqueous liquid formula comprises 0.10% to 4.00% hydrophobic active pharmaceutical ingredient, 28.00% to 99.90% hydrophobic liquid solubilizer, and 0 to 70.00% nonionic surfactant, and 0 to 1.00% antioxidant.
  • the percentages refer to the weight percentages, accounting for the non-aqueous liquid formula
  • the hydrophobic liquid solubilizer comprises medium-chain mono-/diglyceride, and/or propylene glycol fatty acid monoester.
  • a solid microparticle which is composed of porous solid particle and a non-aqueous liquid formulation.
  • the non-aqueous liquid formula is composed of 0.10% to 4.00% hydrophobic active pharmaceutical ingredient, 28.00% to 99.90% hydrophobic liquid solubilizer, and 0 to 70.00% nonionic surfactant, and 0 to 1.00% antioxidant.
  • the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • the hydrophobic liquid solubilizer is composed of medium-chain mono-/di- glyceride, and/or propylene glycol fatty acid monoester.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the filling volume of the solid microparticle of the present invention is significantly smaller.
  • the hard capsules of the present invention can also overcome the following disadvantages of soft gelatin capsules, including higher moisture content which is detrimental to moisture-sensitive products, additional impurities generated by migration of plasticizers to the fillers, and the manufacture process including three to seven days of tray drying.
  • the present invention is further described by the following embodiments.
  • the present invention is not limited to the scope of the embodiments.
  • the experimental methods without indicating specific conditions are performed under conventional methods and conditions, or according to product specifications.
  • the hydrophobic liquid solubilizers were mixed with Fujicalin at a weight ratio of 2: 1, and the flowability of the solid microparticles were estimated by measuring the tap density and bulk density of the solid microparticles.
  • C.I. compression index
  • H.R. Hausner ratio
  • V 0 and V f are the bulk density and the tap density of the solid microparticles, respectively.
  • Hydrophobic liquid solubilizer Weight ratio of Fujicalin/non-aqueous liquid formula Silicon dioxide (%) Bulk density (g/mL) Tap density (g/mL) compressibility index Hausner ratio Embodiment 1-1 Propylene glycol monolaurate (type II) (LAUROGLYCO L 90) 2:1 0 0.685 0.748 8.50 1.09 Embodiment 1-2 Propylene glycol monocaprylate (type II) (CAPRYOL 90) 2:1 0 0.690 0.771 10.5 1.12 Embodiment 1-3 Caprylic capric mono-/diglyceride (type I) (Capmul MCM) 2:1 0 0.690 0.759 9.0 1.10
  • Capryol 90 and Kolliphor® ELP were mixed at a weight ratio of 1: 1, mixed with Fujicalin, and then mixed with silicon dioxide at different weight ratios.
  • the flowability of the solid microparticles were estimated by measuring the tap density and the bulk density of the solid.
  • the obtained solid microparticles with dutasteride solid microparticle formulas shown in Table 4 had a Hausner ratio of 1.00 to 1.18 and good flowability.
  • the obtained solid microparticles with dutasteride solid microparticle formulas shown in Table 4 were made into hard capsule formulations according to the preparation method of embodiment 4, and the dissolution thereof were detected according to the detection method in embodiment 4. They had about the same dissolutions as that of the formulation A-2, and could release about 18% to 25% faster than the reference listed formulation Avodart within 0-15 minutes.
  • Dutasteride solid microparticle hard capsules were prepared, the formulations of the Dutasteride were shown as follows: Table 5: Compositions of the hard capsules in embodiment 4 / Formulation AB Formulation A-1 Formulation A-2 Formulation A-3 Component wt% wt/ capsule mg wt% wt/ capsule mg wt% wt/ capsule mg wt% wt/capsule mg Dutasteride 0.33 0.50 0.33 0.50 0.33 0.50 0.33 0.50 0.50 CAPRYOL 90 33.00 50.00 24.75 37.50 16.50 25.00 13.20 20.00 LABASOL ALF / / 8.25 12.50 16.50 25.00 19.80 30.00 Fujicalin 66.67 101.00 66.67 101.00 66.67 101.00 66.67 101.00 Total 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.
  • the obtained hard capsules of each formula in this embodiment and commercially available Avodart® were stirred at 75 rpm according to USP II (paddle method) with 900mL 0.001N HCl, 1% cetyltrimethylammonium bromide (CTAB) solution as a dissolution medium at a temperature of 37 ⁇ 0.5°C, and sampled at 15 min, 30 min, 45 min, and 60 min.
  • CTAB cetyltrimethylammonium bromide
  • the obtained sample solutions were filtered with a 0.45 ⁇ m filter membrane, and quantitatively detected by an HPLC method.
  • the dissolution of dutasteride were calculated.
  • the chromatographic conditions are shown in Table 6, and the dissolution data are shown in Fig. 1 .
  • formulations AB, A-1, A-2 and A-3 of the present invention could release about 18% to 25% faster than the reference listed formulation Avodart within 0-15 minutes.
  • dutasteride formulations are shown as follows:
  • compositions of hard capsules in embodiment 5 / Formulation B-1 Formulation B-2 Formulation B-3 Component wt% wt/capsule mg wt% wt/capsule mg wt% wt/capsule mg Dutasteride 0.33 0.50 0.33 0.50 0.33 0.50 CAPRYOL 90 24.75 37.50 16.50 25.00 13.20 20.00 Kolliphor®ELP 8.25 12.50 16.50 25.00 19.80 30.00 Fujicalin 66.67 101.00 66.67 101.00 66.67 101.00 Total 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.50
  • the preparation process and dissolution rate detection were the same as those in embodiment 4.
  • the dissolution data are shown in Fig. 2 .
  • the formulations B-1, B-2 and B-3 of the present invention could release about 11% to 30% faster than that of the reference listed formulation Avodart within 0 to 15min, and the formulations B-1 and B-2 could release a little faster than Avodart within 0 to 60min.
  • the formulation B-2 obtained in embodiment 5 and commercially available Avodart® were stirred at 75 rpm according to USP II (paddle method) with 900mL 0.1N HCl, 1% cetyltrimethylammonium bromide (CTAB) solution as a dissolution medium at a temperature of 37 ⁇ 0.5°C.
  • the dissolution medium might or might not contain 0.40% pepsin.
  • the detection method was the same as that in embodiment 4.
  • the dissolution data are shown in Fig. 3 and 4 .
  • Fig. 3 showed that the formulation B-2 obtained in the embodiment 5 had faster release rate and cumulative dissolution than Avodart® in the dissolution medium without pepsin.
  • Fig. 4 showed that the formulation B-2 obtained in the embodiment 5 had about the same dissolution curves of hard capsules and soft capsules as those of Avodart® in the dissolution medium containing pepsin.
  • dutasteride in the hard capsules of the formulation B-2 showed more consistent dissolution rates without being influenced by the presence of pepsin in the dissolution medium, which might be caused by the potential cross-linking of the Avodart® soft gelatin capsules, resulting in that the dissolution of the medicament depended on pepsin.
  • 171.6 mg tamsulosin sustained-release pills and 150 mg dutasteride solid microparticles were prepared and filled together into 0 # hard gelatin capsules. Each capsule contained 0.4 mg tamsulosin and 0.5 mg dutasteride.
  • the formulations of the dutasteride were shown as follows: Table 8: Compositions of hard capsules in embodiment 8 Formulation B-4 Formulation B-5 Component wt% wt/capsule mg wt% wt/ capsule mg Dutasteride 0.33 0.50 0.33 0.50 CAPRYOL 90 24.50 37.12 16.34 24.76 Kolliphor®ELP 8.17 12.38 16.33 24.74 Fujicalin 66.67 101.00 66.67 101.00 BHT 0.33 0.50 0.33 0.50 Total 100.00 151.50 100.00 151.50
  • the dissolution data of the formulation B-4 was similar to that of the formulation B-1 in the embodiment 5, and the dissolution data of the formulation B-5 was similar to that of the formulation B-2 in the embodiment 5.
  • dutasteride solid microparticle hard capsules were prepared according to the formulas in the table below. The preparation process and detection method were the same as those in the embodiment 4.
  • Captex® 355 are triglycerides of caprylic acid (Cs) and capric acid (C 10 ).
  • Table 9 Component wt% wt/capsule mg Dutasteride 0.33 0.50 CAPRYOL 90 24.75 37.50 Captex®355 8.25 12.50 Fujicalin 66.67 101.00 Total 100.00 151.50
  • the self-emulsifying property of the prepared dutasteride solid microparticles were significantly lower than that of the dutasteride solid microparticles of the present application, and the dissolution rate thereof was also significantly lower than that of the dutasteride solid microparticles of the present application.

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Abstract

A solid particle, a preparation method therefor, and a pharmaceutical composition. The solid particle comprises a porous solid particle and a non-aqueous liquid formula. The non-aqueous liquid formula comprises 0.10-4.00 wt% of a hydrophobic active pharmaceutical agent, 28.00-99.90 wt% of a hydrophobic solubilizing solution, 0-70.00 wt% of a non-ionic surfactant, and 0-1.00 wt% of an antioxidant. The hydrophobic solubilizing solution comprises a medium-chain monoglyceride and diglyceride, and/or a propylene glycol fatty acid monoester.

Description

  • The present application claims the priority of Chinese patent application No. CN201810023696.8, filed on January 10th, 2018 , the contents of which are incorporated herein by reference in their entireties.
    • Field of invention
  • The present invention relates to a solid microparticle, a preparation method therefor and a pharmaceutical composition containing the same.
    • Prior arts
  • Avodart® soft gelatin capsules manufactured by Glaxo Smithkline Pharmaceuticals are used for treating benign prostatic hyperplasia (BPH) of men's enlarged prostate. Avodart®'s active ingredient is dutasteride. Dutasteride is a selective steroid 5a-reductase inhibitor, and 5a-reductase is an endoenzyme that can convert testosterone to DHT. Dutasteride has a chemical name of (5α,17β)-N-{2,5-bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxam ide, the empirical formula of which is C27H30F6N2O2, molecular weight of which is 528.5, and the structural formula of which is shown as follows:
    Figure imgb0001
  • Dutasteride is a white to pale yellow powder with a melting point of 242 °C to 250 °C. It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water.
  • Hydrophobic active pharmaceutical ingredients (active pharmaceutical agents, APIs), such as dutasteride, have low bioavailability due to their poor solubility in an aqueous medium such as the gastrointestinal tract and solubilization techniques are commonly used to solve this problem. Commercial available Avodart® soft gelatin capsule contains 0.5 mg dutasteride, which is dissolved in a mixture of caprylic/capric mono-/di-glyceride and dibutylhydroxytoluene.
  • U.S. patent application 20130052263 discloses a formula capable of increasing the solubility of hydrophobic compounds including dutasteride.
  • The manufacturing process of soft capsules is complicated and with high cost and low efficiency. In addition, soft capsules may be compromised in their integrity or lead to delayed dissolution during storage. The main reason for this phenomenon is the crosslinking and aging of the gelatin of the capsule shells, which forms a large network structure, thereby causing the soft capsule to rely on pepsin environment, otherwise pharmaceutical absorption will be affected. Therefore, U.S. Patent 9,622,981 discloses a liquid-filled hard gelatin capsule formulation that can reduce the manufacturing cost of soft capsules while maintain the bioavailability and stability of the soft gel dosage form. However, the liquid-filled hard capsules require a sealing step to prevent potential liquid leakage during manufacturing and storing period. In addition, the moisture in the hard capsules will migrate to the filled liquid formulation, resulting in a decrease in the moisture content of the hard capsules, which may cause the hard capsules to crack.
  • U.S. Patent 9,005,608 discloses a formulation for delivering the beneficial medicament Coenzyme Q (CoQ10), and the recrystallisation of dissolved CoQ10 can be prevented by incorporating a supersaturated self-emulsifying formula of CoQ10 into the pores of porous solid particles.
  • Another commercial product, Jalyn® capsules, manufactured by Glaxo Smithkline Pharmaceuticals, is a pharmaceutical composition of dutasteride and tamsulosin, which can be used for treating benign prostatic hyperplasia (BPH). Tamsulosin is an α1A adrenergic receptor antagonist. Each Jalyn® capsule contains dutasteride soft gelatin capsules and tamsulosin hydrochloride pills, and the capsules and pills are encapsulated in hard shell capsules of # 00 size. Although the combined product showed better treatment efficacy than the individual products, the # 00 size of Jalyn® capsules reached the maximum value recommended by the FDA. Therefore, they are difficult to be swallowed by BPH patients, especially elderly patients.
  • Therefore, there is a need for a new oral dosage form that can accommodate the combination of dutasteride and tamsulosin in a hard capsule, which has a size significantly smaller than the Jalyn capsule, and are bioequivalent to Jalyn® capsules.
    • Content of the present invention
  • The technical problem to be solved by the present invention is to provide a solid microparticle, a preparation method therefor and a pharmaceutical composition containing the same to overcome the disadvantages of the hydrophobic active pharmaceutical ingredients (active pharmaceutical agents, APIs) in the prior art, such as dutasteride, etc., which have low bioavailability, large dosage form size, poor patient compliance, etc.. The solid microparticle can effectively improve solubility of APIs and dissolution rate of medicaments, and can effectively improve the problems of easy cross-linking of soft capsules of commercialized products Avodart® and Jalyn® and oversized dosage form of Jalyn® simultaneously.
  • The present invention provides a solid microparticle, which comprises porous solid particles and a non-aqueous liquid formula, the non-aqueous liquid formula comprises 0.10% to 4.00% hydrophobic active pharmaceutical ingredient, 28.00% to 99.90% hydrophobic liquid solubilizer, 0 to 70.00% nonionic surfactant, and 0 to 1.00% antioxidant, the percentages refer to the weight percentages accounting for the non-aqueous liquid formula; and the hydrophobic liquid solubilizer comprises medium-chain mono-/di- glyceride, and/or propylene glycol fatty acid monoester.
  • In the present invention, the content of the hydrophobic active pharmaceutical ingredient may be 0.10% to 2.00% or 0.18% to 2.00%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • In the present invention, the content of the hydrophobic active pharmaceutical ingredient may be 0.18%, 0.83%, 0.84%, 0.91%, 0.93%, 0.99%, 1.00%, 1.08%, 1.09%, 1.23%, 1.25%, 1.64%, 1.67%, 1.96% or 2.00%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • In the present invention, the content of the hydrophobic liquid solubilizer may be 32.50% to 99.07%, 39.60% to 99.01%, or 49.50% to 74.26%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • In the present invention, the content of the hydrophobic liquid solubilizer may be 32.50%, 39.60%, 46.00%, 47.06%, 49.02%, 49.18%, 49.50%, 59.41%, 59.87%, 60.67%, 60.83%, 61.73%, 63.00%, 65.57%, 72.55%, 73.51%, 74.26%, 75.00%, 82.16%, 82.43%, 83.33%, 98.27%, 98.79%, 99.01% or 99.07%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • In the present invention, when the content of the nonionic surfactant is not 0, the content of the nonionic surfactant may be 15.00% to 66.67%, 24.51% to 59.41%, or 24.75% to 49.50%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • In the present invention, when the content of the nonionic surfactant is not 0, the content of the nonionic surfactant may be 15.00%, 16.43%, 16.49%, 23.75%, 24.51%, 24.75%, 27.27%, 32.79%, 36.00%, 37.04%, 38.33%, 38.79%, 39.60%, 48.99%, 49.18%, 49.50%, 50.98%, 52.00%, 59.41% or 66.67%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • In the present invention, when the content of the antioxidant is not 0, the content of the antioxidant may be 0.10% to 1.00% or 0.17% to 0.83%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • In the present invention, when the content of the antioxidant is not 0, the content of the antioxidant may be 0.17%, 0.28%, 0.33%, 0.51%, 0.83%, or 1.00%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • In a preferred embodiment of the present invention, the non-aqueous liquid formula comprises 0.10% to 2.00% hydrophobic active pharmaceutical ingredient, 97.00% to 99.80% medium-chain mono-/di- glyceride, and 0.10% to 1.00% antioxidant, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • In a preferred embodiment of the present invention, the non-aqueous liquid formula comprises 0.10% to 4.00% hydrophobic active pharmaceutical ingredient, 95.00% to 99.90% propylene glycol fatty acid monoester, and 0 to 1.00% antioxidant, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  • In a preferred embodiment of the present invention, the weight ratio of the porous solid particle to the non-aqueous liquid formula may be a conventional ratio in the art, preferably 2: 1 to 3: 1, and more preferably 2: 1.
  • In a preferred embodiment of the present invention, the solid microparticle comprises 0.025% to 3.00% hydrophobic active pharmaceutical ingredient, 5.00% to 59.90% hydrophobic liquid solubilizer, and 0 to 45.00% nonionic surfactant, 0 to 0.60% antioxidant, and 40.00% to 75.00% porous solid particle, and the percentages refers to the weight percentages accounting for the solid microparticle.
  • In the present invention, the content of the hydrophobic active pharmaceutical ingredient may be 0.10% to 2.00%, such as 0.33%, 0.10% or 0.5%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, the content of the hydrophobic liquid solubilizer may be 5.00% to 39.90%, 11.50% to 35.00% or 13.20% to 33.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, the content of the hydrophobic liquid solubilizer may be 11.50%, 12.00%, 13.20%, 15.00%, 16.34%, 16.50%, 20.00%, 24.50%, 24.75%, 25.00%, 30.00%, 31.50%, 33.00%, 35.00%, 35.50%, 35.70%, 36.40%, 36.50% or 39.90%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, when the hydrophobic liquid solubilizer is medium-chain mono-/di-glyceride, the content of the hydrophobic active pharmaceutical ingredient is preferably 0.025% to 1.20%, and the content of the medium-chain mono-/di-glyceride is 24.50% to 59.90%, for example, 25.00% or 30.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, when the hydrophobic liquid solubilizer is propylene glycol fatty acid monoester, the content of the hydrophobic active pharmaceutical ingredient is preferably 0.025% to 2.40%, and the content of the propylene glycol fatty acid monoester is preferably 23.00% to 59.90%, such as 24.50%, 24.75%, 25.00%, 30.00%, 31.50%, 33.00%, 35.00%, 35.50%, 35.70%, 36.40%, 36.50% or 39.90%, and the percentages refer to the weight percentages account for the solid microparticle.
  • In the present invention, the content of the nonionic surfactant may be 0 to 40.00%. When the content of the nonionic surfactant is not 0, the content of the nonionic surfactant may be 4.50% to 40.00%, 8.17% to 19.80%, or 8.25% to 16.50%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, when the content of the nonionic surfactant is not 0, the content of the nonionic surfactant may be 4.50%, 5.00%, 8.17%, 8.25%, 9.50%, 10.00%, 13.00%, 15.00%, 16.33%, 16.50%, 18.00%, 19.80%, 20.00%, 23.00% or 40.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, when the content of the antioxidant is not 0, the content of the antioxidant may be 0.025% to 0.60%, such as 0.10%, 0.30%, or 0.33%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, the content of the porous solid particles may be 40.00% to 75.00% or 60.00% to 70.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, the content of the porous solid particles may be 40.00%, 40.70%, 45.00%, 49.50%, 50.00%, 59.50%, 60.00%, 63.67%, 64.57%, 64.67%, 66.67%, 69.5%, 69.57%, 69.67%, 70.00%, 74.50% or 75.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, the content of the non-aqueous liquid formula may be 25.00% to 60.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, the content of the non-aqueous liquid formula may be 25.00%, 25.50%, 30.00%, 30.33%, 30.43%, 30.50%, 33.33%, 35.33%, 35.43%, 36.33%, 40.00%, 40.50%, 50.00%, 50.50%, 55.00%, 59.30% or 60.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  • In the present invention, the hydrophobic active pharmaceutical ingredient may be one or more than one selected from dutasteride, finasteride, carvedilol, isotretinoin, fentanyl, sufentanil, zaleplon, testosterone, progesterone, hydroxyprogesterone, norprogesterone, norgestrel, chlorothiazide, furosemide, prednisolone, hydrocortisone, betamethasone, danazol, phenytoin, digoxin, dipyridamole, mefenamic acid, griseofulvin, ketoconazole, itraconazole, glibenclamide, and β-carotene, preferably dutasteride.
  • In the present invention, the medium-chain mono-/di-glyceride refers to an ester chain formed by the esterification of glycerol with one or two C6-C12 fatty acids. Commercially available medium-chain mono-/di- glyceride may comprises Capmul@ products manufactured by Abitec.
  • In the present invention, when the hydrophobic liquid solubilizer comprises medium-chain mono-/di- glyceride, the medium-chain of the medium-chain mono-/diglyceride is preferably a C8-C10 fatty acid chain. The medium-chain mono-/diglyceride is preferably mono-/di- caprylate/caprate (Capmul MCM), such as caprylic capric mono-/di- glyceride.
  • In the present invention, the propylene glycol fatty acid monoester refers to an ester chain formed by esterification of propylene glycol with a C6-C12 fatty acid.
  • In the present invention, when the hydrophobic liquid solubilizer comprises propylene glycol fatty acid monoester, the fatty acid of the propylene glycol fatty acid monoester is preferably a C8-C12 fatty acid chain. The propylene glycol fatty acid monoester is preferably propylene glycol monolaurate (type II) (LAUROGLYCOL 90) and/or propylene glycol monocaprylate (type II) (CAPRYOL 90), more preferably propylene glycol monocaprylate (type II) (CAPRYOL 90).
  • In the present invention, the type of the nonionic surfactant is preferably PEGylated type and/or polyol type, and more preferably PEGylated type.
  • Wherein, the PEGylated nonionic surfactant is preferably polyoxyethylene 35 castor oil (Kolliphor® ELP) and/or caprylocaproyl polyoxylglycerides (LABASOL ALF).
  • Wherein, polyol type nonionic surfactant is preferably polysorbate 80 (TM).
  • In the present invention, the antioxidant may be a conventional antioxidant in the art, preferably dibutylhydroxytoluene (BHT) and/or butylhydroxyanisole (BHA), and more preferably dibutylhydroxytoluene (BHT).
  • In the present invention, the porous solid particles may be a kind of conventional porous carrier in the art, and are preferably one or more than one of calcium hydrogen phosphate (Fujicalin), magnesium aluminometasilicate (Neusilin) and silicon dioxide, and more preferably calcium hydrogen phosphate (Fujicalin).
  • In the present invention, preferably, the porous solid particles have a specific surface area of >30 m2/g, and adsorb at least 0.40 mL/g the non-aqueous liquid formula, while maintaining flowability simultaneously.
  • In a preferred embodiment of the present invention, the solid microparticle comprise 0.0025% to 3.00% hydrophobic active pharmaceutical ingredient, 5.00% to 59.90% hydrophobic liquid solubilizer, 0 to 45.00% nonionic surfactant, 0.025% to 0.60% antioxidant, and 40.00% to 75.00% porous solid particles, and the percentages refers to the weight percentages accounting for the solid microparticle.
  • In a preferred embodiment of the present invention, the solid microparticle comprises 0.33% dutasteride, 33.00% propylene glycol monocaprylate (type II) (CAPRYOL 90), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • In a preferred embodiment of the present invention, the solid microparticle comprises 0.33% dutasteride, 24.75% propylene glycol monocaprylate (type II) (CAPRYOL 90), 8.25% caprylocaproyl polyoxylglycerides (LABASOL ALF), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • In a preferred embodiment of the present invention, the solid microparticle comprises 0.33% dutasteride, 16.5% propylene glycol monocaprylate (type II) (CAPRYOL 90), 16.5% caprylocaproyl polyoxylglycerides (LABASOL ALF), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • In a preferred embodiment of the present invention, the solid microparticle comprises 0.33% dutasteride, 13.2% propylene glycol monocaprylate (type II) (CAPRYOL 90), 19.80% caprylocaproyl polyoxylglycerides (LABASOL ALF) and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • In a preferred embodiment of the present invention, the solid microparticle comprises 0.33% dutasteride, 24.75% propylene glycol monocaprylate (type II) (CAPRYOL 90), 8.25% polyoxyethylene 35 castor oil (Kolliphor® ELP), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • In a preferred embodiment of the present invention, the solid microparticle comprises 0.33% dutasteride, 16.50% propylene glycol monocaprylate (type II) (CAPRYOL 90), 16.50% polyoxyethylene 35 castor oil (Kolliphor® ELP), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • In a preferred embodiment of the present invention, the solid microparticle comprises 0.33% dutasteride, 13.20% propylene glycol monocaprylate (type II) (CAPRYOL 90), 19.80% polyoxyethylene 35 castor oil (Kolliphor® ELP), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • In a preferred embodiment of the present invention, the solid microparticle comprises 0.33% dutasteride, 24.50% propylene glycol monocaprylate (type II) (CAPRYOL 90), 8.17% polyoxyethylene 35 castor oil (Kolliphor® ELP), 0.33% dibutylhydroxytoluene (BHT), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid microparticle.
  • In a preferred embodiment of the present invention, the solid microparticle comprises 0.33% dutasteride, 16.34% propylene glycol monocaprylate (type II) (CAPRYOL 90), 16.33% polyoxyethylene 35 castor oil (Kolliphor® ELP), 0.33% dibutylhydroxytoluene (BHT), and 66.67% calcium hydrogen phosphate (Fujicalin), and the percentages refers to the weight percentages accounting for the solid particle.
  • The invention also provides a method for preparing the solid microparticle, which comprises the following steps:
    1. (1) mixing the active pharmaceutical ingredient with the hydrophobic liquid solubilizer to obtain a solution when the solid microparticle does not comprise the nonionic surfactant and the antioxidant;
      or, mixing the nonionic surfactant and/or the antioxidant, and the active pharmaceutical ingredient and the hydrophobic liquid solubilizer to obtain solution A when the solid particle comprises the nonionic surfactant and/or the antioxidant;
    2. (2) mixing the porous solid particles with the solution obtained in step (1);
      or, mixing the porous solid particles with the solution A obtained in step (1).
  • In step (1), the mixing method may be a conventional mixing method in the art, and is preferably vortexing.
  • In step (2), the porous solid particles may further comprise a glidant. The glidant may be a conventional glidant in the art, and is preferably silicon dioxide.
  • The present invention also provides a pharmaceutical composition containing the solid microparticle and tamsulosin.
  • In the present invention, the pharmaceutical composition may be in a conventional dosage form, such as a hard capsule. The preparation method of the hard capsule can be a conventional preparation method in the art, and specifically, the solid microparticle and tamsulosin are filled into two-piece hard capsules.
  • In the present invention, the tamsulosin is a commercially available conventional product in the art, for example, it may be tamsulosin sustained-release pellets or tamsulosin hydrochloride sustained-release pellets.
  • In a preferred embodiment of the present invention, the pharmaceutical composition may also be used in combination, and the solid microparticle in the pharmaceutical composition are preferably dutasteride solid microparticle. The pharmaceutical composition and the tamsulosin sustained-release pellets can be encapsulated in two-piece hard capsules when they are used in combination, and the size of the hard capsule is not greater than # 0.
  • In the present invention, tamsulosin in the pharmaceutical composition can also be replaced with a conventional therapeutic medicament in the art, as long as the therapeutic medicament does not react with the solid microparticle in the present invention and affect the pharmacological activities of the medicament and the solid particle in the present invention.
  • In the present invention, the term "comprise ..." may also be expressed as "composed of".
  • For example, a solid microparticle comprises porous solid particle and a non-aqueous liquid formula. The non-aqueous liquid formula comprises 0.10% to 4.00% hydrophobic active pharmaceutical ingredient, 28.00% to 99.90% hydrophobic liquid solubilizer, and 0 to 70.00% nonionic surfactant, and 0 to 1.00% antioxidant. The percentages refer to the weight percentages, accounting for the non-aqueous liquid formula The hydrophobic liquid solubilizer comprises medium-chain mono-/diglyceride, and/or propylene glycol fatty acid monoester.
  • It can also be expressed as that a solid microparticle, which is composed of porous solid particle and a non-aqueous liquid formulation. The non-aqueous liquid formula is composed of 0.10% to 4.00% hydrophobic active pharmaceutical ingredient, 28.00% to 99.90% hydrophobic liquid solubilizer, and 0 to 70.00% nonionic surfactant, and 0 to 1.00% antioxidant. The percentages refer to the weight percentages accounting for the non-aqueous liquid formula. The hydrophobic liquid solubilizer is composed of medium-chain mono-/di- glyceride, and/or propylene glycol fatty acid monoester.
  • Without violating common knowledge in the art, the above-mentioned various preferred conditions can be optionally combined to obtain preferred embodiments of the present invention.
  • The reagents and raw materials used in the present invention are all commercially available.
  • The advantageous effects achieved by the present invention are as follows:
    1. (1) The solid microparticle of the present invention improves the dissolving rate and dissolution of hydrophobic active pharmaceutical ingredients, such as dutasteride. The dutasteride hard capsule formulation prepared by the present invention has a dissolution about 11% to 30% faster than that of commercially available product Avodart within 0 to 30 minutes.
    2. (2) The solid microparticle of the present invention is made into hard capsules, which can minimize the potential adsorption of hydrophobic active pharmaceutical ingredients, such as dutasteride, on porous solid particles in an aqueous medium with a pH of 3 or more without relying on the pepsin environment.
    3. (3) The method for preparing the hard capsules of the present invention is simple, does not require the use of special equipment, and is suitable for large-scale industrial production. The dutasteride liquid solid microparticle in the present invention can be easily filled into two-piece hard capsules without the requirement of sealing.
  • Compared with liquid-filled hard gelatin capsules ( U.S. Patent No. 9,622,981 ), it effectively solves the potential liquid leakage problem of the two-piece hard gelatin capsule sealed with a ribbon-like polymer.
  • Compared to soft gelatin capsules, the filling volume of the solid microparticle of the present invention is significantly smaller. In addition, the hard capsules of the present invention can also overcome the following disadvantages of soft gelatin capsules, including higher moisture content which is detrimental to moisture-sensitive products, additional impurities generated by migration of plasticizers to the fillers, and the manufacture process including three to seven days of tray drying.
    • Brief description of the drawings
  • Fig.1 is a dutasteride dissolution curve figure of each formulation in embodiment 4 and the commercial product Avodart® in a dissolution medium at pH = 3.
  • Fig.2 is a dutasteride dissolution curve figure of each formulation in embodiment 5 and the commercial product Avodart® in a dissolution medium at pH = 3.
  • Fig.3 is a dutasteride dissolution curve figure of formulation in embodiment 6 and the commercial product Avodart® in a dissolution medium without pepsin at pH=1.
  • Fig.4 is a dutasteride dissolution curve figure of formulation in embodiment 6 and the commercial product Avodart® in a dissolution medium containing pepsin at pH=1.
    • Detailed description of the preferred embodiment
  • The present invention is further described by the following embodiments. The present invention is not limited to the scope of the embodiments. The experimental methods without indicating specific conditions are performed under conventional methods and conditions, or according to product specifications.
    • Embodiment 1
  • The hydrophobic liquid solubilizers were mixed with Fujicalin at a weight ratio of 2: 1, and the flowability of the solid microparticles were estimated by measuring the tap density and bulk density of the solid microparticles.
  • The compression index (C.I.) and Hausner ratio (H.R.) could be calculated according to the following formula. C . I . = 100 × V 0 − V f / V 0
    Figure imgb0002
     H . R . = V 0 / V f
    Figure imgb0003
  • Wherein V 0 and Vf are the bulk density and the tap density of the solid microparticles, respectively.
  • U.S. Pharmacopeia Chapter 39 <1174 "Powder Flow"> shows the correlation between the powder flowability with the compressibility index and the Hausner ratio (Table 1). Table 1: Flowability and the corresponding compressibility index and Hausner ratio
    Compressibility index (%) Flowability Hausner ratio
    ≤ 10 Excellent 1.00-1.11
    11-15 Good 1.12-1.18
    16-20 Fair, no assistance needed 1.19-1.25
    21-15 Passable, may shake 1.26-1.34
    26-31 Poor-must shake, vibrate 1.35-1.45
    32-37 Very poor 1.46-1.59
    >38 Very,very poor >1.60
  • The measurement results are shown in Table 2. All hydrophobic liquid solubilizers, including propylene glycol monolaurate (type II) (LAUROGLYCOL 90), propylene glycol monocaprylate (type II) (CAPRYOL 90), caprylic capric mono-/diglyceride (type I) (Capmul MCM), etc., showed excellent flowability. Table 2: Flowability of the solid microparticles
    No. Hydrophobic liquid solubilizer Weight ratio of Fujicalin/non-aqueous liquid formula Silicon dioxide (%) Bulk density (g/mL) Tap density (g/mL) compressibility index Hausner ratio
    Embodiment 1-1 Propylene glycol monolaurate (type II) (LAUROGLYCO L 90) 2:1 0 0.685 0.748 8.50 1.09
    Embodiment 1-2 Propylene glycol monocaprylate (type II) (CAPRYOL 90) 2:1 0 0.690 0.771 10.5 1.12
    Embodiment 1-3 Caprylic capric mono-/diglyceride (type I) (Capmul MCM) 2:1 0 0.690 0.759 9.0 1.10
    • Embodiment 2
  • Capryol 90 and Kolliphor® ELP were mixed at a weight ratio of 1: 1, mixed with Fujicalin, and then mixed with silicon dioxide at different weight ratios. The flowability of the solid microparticles were estimated by measuring the tap density and the bulk density of the solid.
  • According to the measurement results shown in Table 3, silicon dioxide-free solid microparticles with a Fujicalin to non-aqueous liquid formula weight ratio of 2: 1 or 3: 1 had excellent flowability. Table 3: Flowability of the solid microparticles
    No. Weight ratio of Fujicalin/non-aqueous liquid formula Silicon dioxide (%) Bulk density (g/mL) Tap density (g/mL) compressibility index Hausner ratio
    Embodiment 2-1 2:1 1.0 0.629 0.718 12.5 1.14
    Embodiment 2-2 2:1 0.25 0.675 0.749 10.0 1.11
    Embodiment 2-3 2:1 0 0.696 0.765 9.0 1.10
    Embodiment 2-4 3:1 0 0.627 0.681 8.0 1.09
    Comparative embodiment 1 1:0 0 0.479 0.529 9.5 1.10
    • Embodiment 3
  • When the solid microparticles were prepared, the content of each component might be as shown in the following table, the percentages referred to the weight percentages accounting for solid microparticles. Table 4
    No. Hydrophobic active pharmaceutical agent Hydrophobic liquid solubilizer Nonionic surfactant Antioxidant Porous solid particles
    Embodiment 3-1 0.33% dutasteride 35.00% CAPRYOL 90 / / 64.67% Fujicalin
    Embodiment 3-2 0.33% dutasteride 35.00% CAPRYOL 90 / 0.10% BHT 64.57% Fujicalin
    Embodiment 3-3 0.33% dutasteride 35.7% CAPRYOL 90 / 0.30% BHT 63.67% Fujicalin
    Embodiment 3-4 0.33% dutasteride 35.00% CAPRYOL 90 / 0.10% BHT 34.57% Fujicalin and 30% silicon dioxide
    Embodiment 3-5 0.33% dutasteride 25.00% CAPRYOL 90 5.00% Kolliphor®ELP / 69.67% Fujicalin
    Embodiment 3-6 0.33% dutasteride 25.00% CAPRYOL 90 5.00% LABASOL ALF / 69.67% Fujicalin
    Embodiment 3-7 0.33% dutasteride 25.00% CAPRYOL 90 5.00% Polysorbate 80 TM / 69.67% Fujicalin
    Embodiment 3-8 0.33% dutasteride 25.00% CAPRYOL 90 5.00% Kolliphor®ELP 0.10% BHT 69.57% Fujicalin
    Embodiment 3-9 0.33% dutasteride 25.00% CAPRYOL 90 5.00% LABASOL ALF 0.10% BHT 69.57% Fujicalin
    Embodiment 3-10 0.33% dutasteride 25.00% CAPRYOL 90 5.00% Polysorbate 80 TM 0.10% BHT 69.57% Fujicalin
    Embodiment 3-11 0.33% dutasteride 25.00% CAPRYOL 90 5.00% Polysorbate 80 TM 0.10% BHT 69.57% Neusilin
    Embodiment 3-12 0.10% dutasteride 39.90% CAPRYOL 90 15.00% Polysorbate 80 TM / 45.00% Fujicalin
    Embodiment 3-13 0.50% dutasteride 20.00% CAPRYOL 90 10.00% Polysorbate 80 TM / 69.50% Fujicalin
    Embodiment 3-14 0.50% dutasteride 11.50% CAPRYOL 90 13.00% Polysorbate 80 TM / 75.00% Fujicalin
    Embodiment 3-15 0.50% dutasteride 25.00% Capmul MCM 4.50% Kolliphor®ELP / 70.00% Fujicalin
    Embodiment 3-16 0.50% dutasteride 12.00% CAPRYOL 90 13.00% Kolliphor®ELP / 74.50% Fujicalin
    Embodiment 3-17 0.50% dutasteride 15.00% CAPRYOL 90 15.00% Kolliphor®ELP / 69.50% Fujicalin
    Embodiment 3-18 0.50% dutasteride 25.00% CAPRYOL 90 15.00% Kolliphor®ELP / 59.50% Fujicalin
    Embodiment 3-19 0.50% dutasteride 30.00% CAPRYOL 90 20.00% Kolliphor®ELP / 49.50% Fujicalin
    Embodiment 3-20 0.50% dutasteride 19.50% CAPRYOL 90 40.00% Kolliphor®ELP / 40.00% Fujicalin
    Embodiment 3-21 0.50% dutasteride 30.00% Capmul MCM 9.50% Kolliphor®ELP / 60.00% Fujicalin
    Embodiment 3-22 0.50% dutasteride 31.50% LAUROGLYC OL 90 18.00% LABASOL ALF / 50.00% Fujicalin
    Embodiment 3-23 0.50% dutasteride 36.50% LAUROGLYC OL 90 23.00% LABASOL ALF / 40.00% Fujicalin
    Embodiment 3-24 0.50% dutasteride 36.40% LAUROGLYC OL 90 23.00% LABASOL ALF 0.10% BHT 40.00% Fujicalin
    Embodiment 3-25 0.50% dutasteride 35.50% LAUROGLYC OL 90 23.00% LABASOL ALF 0.30% BHT 40.70% Fujicalin
  • The obtained solid microparticles with dutasteride solid microparticle formulas shown in Table 4 had a Hausner ratio of 1.00 to 1.18 and good flowability.
  • The obtained solid microparticles with dutasteride solid microparticle formulas shown in Table 4 were made into hard capsule formulations according to the preparation method of embodiment 4, and the dissolution thereof were detected according to the detection method in embodiment 4. They had about the same dissolutions as that of the formulation A-2, and could release about 18% to 25% faster than the reference listed formulation Avodart within 0-15 minutes.
    • Embodiment 4
  • Dutasteride solid microparticle hard capsules were prepared, the formulations of the Dutasteride were shown as follows: Table 5: Compositions of the hard capsules in embodiment 4
    / Formulation AB Formulation A-1 Formulation A-2 Formulation A-3
    Component wt% wt/ capsule mg wt% wt/ capsule mg wt% wt/ capsule mg wt% wt/capsule mg
    Dutasteride 0.33 0.50 0.33 0.50 0.33 0.50 0.33 0.50
    CAPRYOL 90 33.00 50.00 24.75 37.50 16.50 25.00 13.20 20.00
    LABASOL ALF / / 8.25 12.50 16.50 25.00 19.80 30.00
    Fujicalin 66.67 101.00 66.67 101.00 66.67 101.00 66.67 101.00
    Total 100.00 151.50 100.00 151.50 100.00 151.50 100.00 151.50
  • Preparation process of the capsules:
    1. (1) prescribed amounts of dutasteride and CAPRYOL 90 were mixed and vortexed for 5 minutes;
    2. (2) a prescribed amount of surfactant LABASOL ALF was added to obtain a clear solution;
    3. (3) the solution was mixed with porous particles to obtain solid microparticles capable of flowing freely;
    4. (4) 151mg solid microparticles were filled into # 2 hard capsules. Each capsule contained 0.5mg dutasteride.
    Measurement of dissolution:
  • The obtained hard capsules of each formula in this embodiment and commercially available Avodart® were stirred at 75 rpm according to USP II (paddle method) with 900mL 0.001N HCl, 1% cetyltrimethylammonium bromide (CTAB) solution as a dissolution medium at a temperature of 37±0.5°C, and sampled at 15 min, 30 min, 45 min, and 60 min. The obtained sample solutions were filtered with a 0.45µm filter membrane, and quantitatively detected by an HPLC method. The dissolution of dutasteride were calculated. The chromatographic conditions are shown in Table 6, and the dissolution data are shown in Fig. 1. Table 6: HPLC chromatographic conditions
    Instrument
    Waters LC aqueous liquid chromatography with automatic sampling, injection and UV detection
    Column
    Thermo AQUASIL C18 0.46* 150mm, 5µm
    Operation parameters:
    Mobile phase: acetonitrile, methanol and water (40: 20: 35)
    Injection volume: 100 µL
    Flow rate: 2.0 mL/min
    Column temperature: 35°C
    Detector wavelength: UV 240 nm
  • Conclusion: the formulations AB, A-1, A-2 and A-3 of the present invention could release about 18% to 25% faster than the reference listed formulation Avodart within 0-15 minutes.
    • Embodiment 5 The formulas of dutasteride formulations are shown as follows:
  • Table 7: compositions of hard capsules in embodiment 5
    / Formulation B-1 Formulation B-2 Formulation B-3
    Component wt% wt/capsule mg wt% wt/capsule mg wt% wt/capsule mg
    Dutasteride 0.33 0.50 0.33 0.50 0.33 0.50
    CAPRYOL 90 24.75 37.50 16.50 25.00 13.20 20.00
    Kolliphor®ELP 8.25 12.50 16.50 25.00 19.80 30.00
    Fujicalin 66.67 101.00 66.67 101.00 66.67 101.00
    Total 100.00 151.50 100.00 151.50 100.00 151.50
  • The preparation process and dissolution rate detection were the same as those in embodiment 4. The dissolution data are shown in Fig. 2.
  • Conclusions: the formulations B-1, B-2 and B-3 of the present invention could release about 11% to 30% faster than that of the reference listed formulation Avodart within 0 to 15min, and the formulations B-1 and B-2 could release a little faster than Avodart within 0 to 60min.
    • Embodiment 6
  • The formulation B-2 obtained in embodiment 5 and commercially available Avodart® were stirred at 75 rpm according to USP II (paddle method) with 900mL 0.1N HCl, 1% cetyltrimethylammonium bromide (CTAB) solution as a dissolution medium at a temperature of 37±0.5°C. The dissolution medium might or might not contain 0.40% pepsin.
  • The detection method was the same as that in embodiment 4. The dissolution data are shown in Fig. 3 and 4.
    • Conclusions:
  • Fig. 3 showed that the formulation B-2 obtained in the embodiment 5 had faster release rate and cumulative dissolution than Avodart® in the dissolution medium without pepsin.
  • Fig. 4 showed that the formulation B-2 obtained in the embodiment 5 had about the same dissolution curves of hard capsules and soft capsules as those of Avodart® in the dissolution medium containing pepsin.
  • Compared with Avodart® gelatin soft capsules, dutasteride in the hard capsules of the formulation B-2 showed more consistent dissolution rates without being influenced by the presence of pepsin in the dissolution medium, which might be caused by the potential cross-linking of the Avodart® soft gelatin capsules, resulting in that the dissolution of the medicament depended on pepsin.
    • Embodiment 7
  • According to the formula and preparation method of embodiment 5, 171.6 mg tamsulosin sustained-release pills and 150 mg dutasteride solid microparticles (formulation B-2) were prepared and filled together into 0 # hard gelatin capsules. Each capsule contained 0.4 mg tamsulosin and 0.5 mg dutasteride.
    • Embodiment 8
  • The formulations of the dutasteride were shown as follows: Table 8: Compositions of hard capsules in embodiment 8
    Formulation B-4 Formulation B-5
    Component wt% wt/capsule mg wt% wt/ capsule mg
    Dutasteride 0.33 0.50 0.33 0.50
    CAPRYOL 90 24.50 37.12 16.34 24.76
    Kolliphor®ELP 8.17 12.38 16.33 24.74
    Fujicalin 66.67 101.00 66.67 101.00
    BHT 0.33 0.50 0.33 0.50
    Total 100.00 151.50 100.00 151.50
  • The preparation process and detection of dissolution were the same as those in the embodiment 4.
  • The dissolution data of the formulation B-4 was similar to that of the formulation B-1 in the embodiment 5, and the dissolution data of the formulation B-5 was similar to that of the formulation B-2 in the embodiment 5.
    • Comparative embodiment 2
  • The dutasteride solid microparticle hard capsules were prepared according to the formulas in the table below. The preparation process and detection method were the same as those in the embodiment 4. Captex® 355 are triglycerides of caprylic acid (Cs) and capric acid (C10). Table 9
    Component wt% wt/capsule mg
    Dutasteride 0.33 0.50
    CAPRYOL 90 24.75 37.50
    Captex®355 8.25 12.50
    Fujicalin 66.67 101.00
    Total 100.00 151.50
  • When the hydrophobic liquid solubilizer comprised medium-chain triglycerides, the self-emulsifying property of the prepared dutasteride solid microparticles were significantly lower than that of the dutasteride solid microparticles of the present application, and the dissolution rate thereof was also significantly lower than that of the dutasteride solid microparticles of the present application.
  • Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are merely for illustration, and that various changes or modifications may be made to these embodiments without departing from the principle and essence of the present invention. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims (10)

  1. A solid microparticle, which comprises porous solid particles and a non-aqueous liquid formula, the non-aqueous liquid formula comprises 0.10% to 4.00% hydrophobic active pharmaceutical ingredient, 28.00% to 99.90% hydrophobic liquid solubilizer, 0 to 70.00% nonionic surfactant, and 0 to 1.00% antioxidant, the percentages refer to the weight percentages accounting for the non-aqueous liquid formula; and the hydrophobic liquid solubilizer comprises medium-chain mono-/diglyceride, and/or propylene glycol fatty acid monoester.
  2. The solid microparticle as claimed in claim 1, wherein the content of the hydrophobic active pharmaceutical ingredient is 0.10% to 2.00% or 0.18% to 2.00%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula;
    and/or, the content of the hydrophobic liquid solubilizer is 32.50% to 99.07%, 39.60% to 99.01%, or 49.50% to 74.26%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula;
    and/or, when the content of the nonionic surfactant is not 0, the content of the nonionic surfactant is 15.00% to 66.67%, 24.51% to 59.41%, or 24.75% to 49.50%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula;
    and/or, when the content of the antioxidant is not 0, the content of the antioxidant is 0.10% to 1.00% or 0.17% to 0.83%, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula.
  3. The solid microparticle as claimed in claim 1 or 2, wherein,
    when the hydrophobic liquid solubilizer is medium-chain mono-/di- glyceride, the non-aqueous liquid formula comprises 0.10% to 2.00% hydrophobic active pharmaceutical ingredient, 97.00% to 99.80% medium-chain mono-/di- glyceride, and 0.10% to 1.00% antioxidant, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula;
    and/or, when the hydrophobic liquid solubilizer is propylene glycol fatty acid monoester, the non-aqueous liquid formula comprises 0.10% to 4.00% hydrophobic active pharmaceutical ingredient, 95.00% to 99.90% propylene glycol fatty acid monoester, and 0 to 1.00% antioxidant, and the percentages refer to the weight percentages accounting for the non-aqueous liquid formula;
    and/or, the weight ratio of the porous solid particles to the non-aqueous liquid formula is 2: 1 to 3: 1, preferably 2: 1.
  4. The solid microparticle as claimed in at least one of claims 1 to 3, wherein the solid microparticle comprises 0.025% to 3.00% hydrophobic active pharmaceutical ingredient, 5.00% to 59.90% hydrophobic liquid solubilizer, and 0 to 45.00% nonionic surfactant, 0 to 0.60% antioxidant, and 40.00% to 75.00% porous solid particles, and the percentages refers to the weight percentages accounting for the solid microparticle.
  5. The solid microparticle as claimed in claim 4, wherein the content of the hydrophobic active pharmaceutical ingredient is 0.10% to 2.00%, and the percentages refer to the weight percentages accounting for the solid microparticle;
    and/or, the content of the hydrophobic liquid solubilizer is 5.00% to 39.90%, 11.50% to 35.00%, or 13.20% to 33.00%, and the percentages refer to the weight percentages accounting for the solid microparticle;
    and/or, the content of the nonionic surfactant is 0 to 40.00%, 4.50% to 40.00%, 8.25% to 19.80%, or 8.25% to 16.50%, and the percentages refer to the weight percentages accounting for the solid microparticle;
    and/or, the content of the antioxidant is 0.025% to 0.60%, and the percentages refer to the weight percentages accounting for the solid microparticle;
    and/or, the content of the porous solid particles is 40.00% to 75.00% or 60.00% to 70.00%, and the percentages refer to the weight percentages accounting for the solid microparticle.
  6. The solid microparticle as claimed in claim 4, wherein,
    when the hydrophobic liquid solubilizer is medium-chain mono-/di- glyceride, the content of the hydrophobic active pharmaceutical ingredient is 0.025% to 1.20%, the content of medium-chain mono-/di- glyceride is 24.50% to 59.90%, and the percentages refer to the weight percentages accounting for the solid microparticle;
    and/or, when the hydrophobic liquid solubilizer is propylene glycol fatty acid monoester, the content of the hydrophobic active pharmaceutical ingredient is 0.025% to 2.40%, the content of the propylene glycol fatty acid monoester is 23.00% to 59.90%, and the percentages refer to the weight percentages accounting for the solid microparticle;
    and/or, the solid microparticle comprises 0.0025% to 3.00% hydrophobic active pharmaceutical ingredient, 5.00% to 59.90% hydrophobic liquid solubilizer, 0 to 45.00% nonionic surfactant, 0.025% to 0.60% antioxidant, and 40.00% to 75.00% porous solid particles, and the percentages refers to the weight percentages accounting for the solid microparticle.
  7. The solid microparticle as claimed in at least one of claims 1 to 6, wherein,
    the hydrophobic active pharmaceutical ingredient is one or more of dutasteride, finasteride, carvedilol, isotretinoin, fentanyl, sufentanil, zaleplon, testosterone, progesterone, hydroxyprogesterone, norprogesterone, norgestrel, chlorothiazide, furosemide, prednisolone, hydrocortisone, betamethasone, danazol, phenytoin, digoxin, dipyridamole, mefenamic acid, griseofulvin, ketoconazole, itraconazole, glibenclamide, and β-carotene, preferably dutasteride;
    and/or, when the hydrophobic liquid solubilizer comprises medium-chain mono-/di- glyceride, the medium-chain mono-/di- glyceride is preferably mono-/di-caprylate/caprate, and more preferably caprylic capric mono-/di- glyceride;
    and/or, when the hydrophobic liquid solubilizer comprises propylene glycol fatty acid monoester, the propylene glycol fatty acid monoester is preferably propylene glycol monolaurate type II and/or propylene glycol monocaprylate type II, and more preferably propylene glycol monocaprylate type II;
    and/or, the type of the nonionic surfactant is PEGylated type and/or polyol type, preferably PEGylated type; and the PEGylated type nonionic surfactant is preferably polyoxyethylene 35 castor oil and/or caprylocaproyl polyoxylglycerides; and the polyol type nonionic surfactant is preferably polysorbate 80;
    and/or, the antioxidant is dibutylhydroxytoluene and/or butylhydroxyanisole, preferably dibutylhydroxytoluene;
    and/or, the porous solid particles are one or more than one of calcium hydrogen phosphate, magnesium aluminometasilicate and silicon dioxide, preferably calcium hydrogen phosphate;
    and/or, the porous solid particles have a specific surface area of >30 m2/g, and adsorb at least 0.40 mL/g the non-aqueous liquid formula while maintaining flowability simultaneously.
  8. The solid microparticle as claimed in claim 7, wherein the solid microparticle comprises 0.33% dutasteride, 33.00% propylene glycol monocaprylate type II, and 66.67% calcium hydrogen phosphate, and the percentages refer to the weight percentages accounting for the solid microparticle;
    or, the solid microparticle comprises 0.33% dutasteride, 24.75% propylene glycol monocaprylate type II, 8.25% caprylocaproyl polyoxylglycerides, and 66.67% calcium hydrogen phosphate, and the percentages refer to the weight percentages accounting for the solid microparticle;
    or, the solid microparticle comprises 0.33% dutasteride, 16.50% propylene glycol monocaprylate type II, 16.50% caprylocaproyl polyoxylglycerides, and 66.67% calcium hydrogen phosphate, and the percentages refer to the weight percentages accounting for the solid microparticle;
    or, the solid microparticle comprises 0.33% dutasteride, 13.20% propylene glycol monocaprylate type II, 19.80% caprylocaproyl polyoxylglycerides, and 66.67% calcium hydrogen phosphate, and the percentages refer to the weight percentages accounting for the solid microparticle;
    or, the solid microparticle comprises 0.33% dutasteride, 24.75% propylene glycol monocaprylate type II, 8.25% polyoxyethylene 35 castor oil, and 66.67% calcium hydrogen phosphate, and the percentages refer to the weight percentages accounting for the solid microparticle;
    or, the solid microparticle comprises 0.33% dutasteride, 16.50% propylene glycol monocaprylate type II, 16.50% polyoxyethylene 35 castor oil, and 66.67% calcium hydrogen phosphate, and the percentages refer to the weight percentages accounting for the solid microparticle;
    or, the solid microparticle comprises 0.33% dutasteride, 13.20% propylene glycol monocaprylate type II, 19.80% polyoxyethylene 35 castor oil, and 66.67% calcium hydrogen phosphate, and the percentages refer to the weight percentages accounting for the solid microparticle.
  9. A method for preparing the solid microparticle as claimed in at least one of claims 1 to 8, which comprises the following steps:
    (1) mixing the pharmaceutical active ingredient with the hydrophobic liquid solubilizer to obtain a solution when the solid microparticle do not comprise the nonionic surfactant and the antioxidant;
    or, mixing the nonionic surfactant and/or the antioxidant, and the pharmaceutical active ingredient and the hydrophobic liquid solubilizer to obtain solution A when the solid microparticle comprises the nonionic surfactant and/or the antioxidant;
    (2) mixing the porous solid particles with the solution obtained in step (1);
    or, mixing the porous solid particles with the solution A obtained in step (1).
  10. A pharmaceutical composition comprising the solid microparticle as claimed in at least one of claims 1 to 8 and tamsulosin.
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